Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a dismal therapeutic outcome. This interdisciplinary study aims to develop a new Positron Emission Tomography (PET) assay for patient stratification, which could lead to more efficacious and better tolerated personalized therapies for PDAC. Therapeutic responses to gemcitabine (GEM), the most frequently used chemotherapeutic agent in PDAC, are observed in less than 10% of patients. Amongst proposed reasons for GEM's suboptimal efficacy in PDAC two suggested mechanisms have emerged as leading candidates: (i) suboptimal drug delivery to PDAC tumor cells because of a poorly vascularized and dense tumor-associated stroma and (ii) inefficient uptake and/or conversion of the prodrug GEM to its active, cytotoxic metabolites by the PDAC tumor cells. In support of the former mechanism, new stromal depleting (SD) therapies, such as Abraxane and pegylated hyaluronidase improve GEM delivery to tumor cells, extending survival in preclinical models, and, in the case of Abraxane, in patients. GEM could be used more effectively for PDAC therapy if companion diagnostics are developed to measure if the addition of a SD agent enhances intratumoral GEM delivery and its conversion to therapeutically active metabolites in tumor cells. This proposal will test the hypothesis that a new GEM analog PET probe 1-L-(2-Deoxy-2,-18Fluoro-Arabinofuranosyl) Cytosine (18F-L-FAC) developed by UCLA investigators can be used to determine (1) the shortest schedule of SD agents required to increase GEM delivery to tumor cells, and (2) the efficiency both of intratumoral GEM accumulation and activation by tumor cells in PDAC patients.
In Aim 1, PET will be used to determine, in preclinical models, the shortest schedule of stromal depleting therapy required to induce detectable changes in tumor probe (18F-L-FAC) and drug (GEM) delivery.
Aim 2 proposes study to determine the accuracy of 18F-L-FAC PET measures of intra-tumoral GEM delivery and metabolism in PDAC patients treated with SD therapies. The expected outcome is a new PET assay to identify PDAC patients who are likely responders to GEM administered in combination with SD therapies. This assay will address a currently unmet clinical need in pancreatic cancer management since alternatives to GEM/Abraxane, albeit considerably more toxic for patients, are now available.
Oncologists now face the challenging decision of how to best treat pancreatic cancer given the recent FDA approval of the gemcitabine/Abraxane combination and the emergence of new chemotherapeutic regimens. To address this unmet clinical need and enable a more personalized approach to pancreatic cancer treatment, we will develop a new non-invasive companion biomarker to gemcitabine/Abraxane which will allow the identification of patients who are likely responders to this combination at the beginning of their therapy.
|Garrett, Matthew; Sperry, Jantzen; Braas, Daniel et al. (2018) Metabolic characterization of isocitrate dehydrogenase (IDH) mutant and IDH wildtype gliomaspheres uncovers cell type-specific vulnerabilities. Cancer Metab 6:4|
|Lückerath, Katharina; Stuparu, Andreea D; Wei, Liu et al. (2018) Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer. J Nucl Med 59:1392-1397|
|Antonios, Joseph P; Soto, Horacio; Everson, Richard G et al. (2017) Detection of immune responses after immunotherapy in glioblastoma using PET and MRI. Proc Natl Acad Sci U S A 114:10220-10225|
|Fendler, Wolfgang P; Stuparu, Andreea D; Evans-Axelsson, Susan et al. (2017) Establishing 177Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer. J Nucl Med 58:1786-1792|
|Barrio, Martin J; Spick, Claudio; Radu, Caius G et al. (2017) Human Biodistribution and Radiation Dosimetry of 18F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway. J Nucl Med 58:374-378|
|Sugimoto, Motokazu; Hines, O Joe; Dawson, David W et al. (2017) Preoperative Treatment With FOLFIRINOX and Successful Resection for a Patient With Mixed Acinar-Endocrine Carcinoma of the Pancreas. Pancreas 46:e32-e34|
|Nguyen, Andrew H; Elliott, Irmina A; Wu, Nanping et al. (2017) Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts. Oncotarget 8:19074-19088|
|Le, Thuc M; Poddar, Soumya; Capri, Joseph R et al. (2017) ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways. Nat Commun 8:241|
|Laks, Dan R; Ta, Lisa; Crisman, Thomas J et al. (2016) Inhibition of Nucleotide Synthesis Targets Brain Tumor Stem Cells in a Subset of Glioblastoma. Mol Cancer Ther 15:1271-8|
|Donahue, Timothy R; Dawson, David W (2016) Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality. Trends Endocrinol Metab 27:770-781|
Showing the most recent 10 out of 17 publications